The increase in bacterial resistance to existing antibacterial agents is a major clinical problem. Accordingly, there is a need in the art for compounds, compositions, and methods of treating warm-blooded animals that suffer from a bacterial infection and are resistant to conventional antibacterial treatments. The development and increase in resistance to the quinolone carboxylic acid class of antibacterial compounds has not been as pervasive as with other antibacterial agents. Therefore, new quinolone carboxylic acid compounds may be useful in combating resistant bacteria.
The 7-substituted quinolone carboxylic acid derivatives, represented by the general formula (II), wherein Y is either C—R5 or N, and R1 through R5 include a wide variety of substituents, are well known as anti-fungal and anti-bacterial agents, and as synthetic intermediates to related compounds. The 7-substituted derivatives of compound (II) include the antibacterials cinoxacin (U.S. Pat. No. 3,669,965); ciprofloxacin (U.S. Pat. Nos. 4,563,459 and 4,620,007); ofloxacin (U.S. Pat. No. 4,382,892); and levofloxacin (U.S. Pat. Nos. 4,985,557, 5,053,407, and 5,142,046). 
Oxazolidinones having a general structural formula (III) also are a well known class of orally active, synthetic antibacterial agents. The literature contains numerous references to oxazolidinones (III), wherein R1 through R3 include a wide variety of substituents. Oxazolidinones having one or two substituents on the phenyl ring are disclosed in U.S. Pat. Nos. 4,705,799; 5,523,403; and 5,654,435, for example. Oxazolidinones (III) include the antibacterial agent designated as DuP 721, see J. Med. Chem., 32, 1673 (1989). 
Oxazolidinones (III) having an arylbenzene substituent on the oxazolidinone ring are disclosed in U.S. Pat. Nos. 4,948,801 and 5,130,316. 3-[(Di- or fused-ring substituted)phenyl]-2-oxazolidinones are disclosed in U.S. Pat. Nos. 4,977,173; 4,921,869; 4,801,600; and 5,164,510. European Patent Applications 0 697 412; 0 694 544; 0 694 543; and 0 693 491, and International Patent Publication No. WO 93/09103, disclose 5- to 9-membered substituted aryl- and heteroaryl-phenyl oxazolidinones as antibacterial agents. U.S. Pat. No. 5,254,577 discloses aminomethyloxooxazolidinyl arylbenzene derivatives as antibacterial agents. Other references disclosing oxazolidinones include U.S. Pat. Nos. 4,801,600 and 4,921,869. Some of the pyridine-substituted phenyl oxazolidinone derivatives disclosed in the above patents are effective against Gram positive bacteria, such as Staphylococcus aureus and Streptococcus pneumoniae. However, the oxazolidinones are not active against Gram negative bacteria, such as Escherichia coli, Klebsiella, Proteus, and Seratia marcenses. Moreover, oxazolidinones cannot be administered as an injection solution because their free amino forms are sparingly soluble.
Isoxazolinone derivatives having a general structural formula (IV) are disclosed in WO 00/10566 as anti-bacterial agents. Simple isoxazolinones also are used as preemergent herbicides. For example, U.S. Pat. No. 4,065,463 discloses 2-methyl-4-(chloro-m-tolyl)-3-isoxazolin-5-one, which is useful in preventing weed growth. 
Isoxazoline derivatives having a general structural formula (V) are disclosed in WO 99/41244, WO 98/07708 and U.S. Pat. No. 3,769,295 as anti-microbial agents. Simple isoxazolines also are used as preemergent herbicides. In addition, U.S. Pat. No. 4,283,403 discloses 3-aryl-2-isoxazolines, which are useful in preventing plant fungal diseases. 
Although quinolones, oxazolidinones, isoxazolinones, and isoxazolines are known, applicants are aware of no reference which discloses covalently bonding a quinolone to an oxazolidinone, an isoxazolinone, or an isoxazoline, and using the resulting quinolone derivatives as broad spectrum anti-bacterial agents against both Gram positive and Gram negative bacteria.
The present invention is directed to structurally novel compounds produced by covalently bonding an antibacterial oxazolidinone, isoxazolinone, or isoxazoline compound to a substituted quinolone compound. The compounds of the present invention have a quinolone structure substituted with an oxazolidinone, isoxazolinone, or isoxazoline via a linking group at the 1- or 7-position of the quinolone.
The present compounds are active against Gram negative bacteria and Gram positive bacteria, and accordingly are useful as broad spectrum antibacterial agents. The present compounds are surprisingly effective against a number of human and veterinary pathogens, including Staphylococci, for example S. aureus; Enterococci, for example E. faecalis; Streptococci, for example S. pneumoniae; Haemophilus, for example H. influenza; Moraxella, for example M. catarrhalis; and Escherichia for example E. coli. Other examples include Mycobacteria, for example M. tuberculosis; intercellular microbes, for example Chlamydia and Rickettsiae; and Mycoplasma, for example M. pneumoniae. The present compounds also are envisioned as cytotoxic anticancer agents.
Syntheses of simple quinolone derivatives are well known in the art. However, the synthesis of a quinolone covalently linked to an oxazolidinone, an isoxazolinone, or an isoxazoline is not straightforward. Thus, a method of synthesizing compounds of the present invention also is disclosed.